naphthoquinones and Hypertension

The neuroprotective effects of the course therapy with Histochrome in Wistar rats with modeled arterial hypertension were studied by using magnetic resonance imaging (MRI) in diffusion-weighted mode. The behavioral status of the animals was assessed using the open-field test. MRI analysis revealed more pronounced increase in the signaling characteristics of the brain tissue in hypertensive rats in comparison with the control (intact) animals. It was caused by excessive accumulation of fluid in the intra- and extracellular spaces of the brain tissue, which is associated with hypervolemia induced by the multifactorial cardiovasorenal model of hypertension. After a course of Histochrome injections to hypertensive rats, the cerebral microcirculation disorders were leveled, while the behavioral status was characterized by shortened latency of the visit to the center of the open field by 20% and improvement of cognitive activity (by 1.6 times) and the exploratory component (by 30%).

Topics: Animals; Brain; Hypertension; Magnetic Resonance Imaging; Naphthoquinones; Rats; Rats, Wistar

Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelium, Vascular; Hypertension; Male; Naphthoquinones; Rats; Rats, Sprague-Dawley; Vasodilation

Endothelial nitric oxide synthase (eNOS) is involved in blood pressure (BP) regulation through the production of nitric oxide. Sirtuin I (SIRT1), an NAD-dependent protein deacetylase, promotes vascular relaxation through deacetylation and activation of eNOS. β-Lapachone (βL) increases the cellular NAD(+)/NADH ratio by activating. quinone oxidoreductase 1 (NQO1). In this study, we verified whether activation of NQO1 by βL modulates BP through regulation of eNOS acetylation in a hypertensive animal model.. Spontaneously hypertensive rats (SHRs) and an endothelial cell line (bEnd.3 cells) were used to investigate the hypotensive effect of βL and its mechanism of action.. βL treatment significantly lowered the BP in SHRs, but this hypotensive effect was completely blocked by eNOS inhibition with ω-nitro-l-arginine methyl ester. In vitro studies revealed that βL activated eNOS, which was accompanied by an increased NAD(+)/NADH ratio. Moreover, βL significantly decreased acetylation of eNOS; however, this reduced eNOS acetylation was completely precluded by inhibition of SIRT1 in the bEnd.3 cells and in the aorta of the SHRs. Consistent with these effects, βL-induced reduction in BP was also abolished by SIRT1 inhibition in the SHRs.. To the best of our knowledge, this is the first study to demonstrate that eNOS acetylation can be regulated by NQO1 activation in an SIRT1-dependent manner, which is correlated with the relief of hypertension. These findings provide strong evidence that NQO1 might be a new therapeutic target for hypertension.

Topics: Acetylation; Animals; Antihypertensive Agents; Blood Pressure; Cell Line; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; Humans; Hypertension; Male; Mice; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Nitric Oxide Synthase Type III; Protein Processing, Post-Translational; Rats, Inbred SHR; Sirtuin 1; Time Factors

Magnetic resonance tomography was employed to verify endothelial dysfunction of renal arteries in Wistar and OXYS rats under conditions of induced arterial hypertension. Angiography revealed changes in the size and form of renal arteries of hypertensive animals. In hypertensive rats, histochrome exerted a benevolent therapeutic effect in renal arteries: it decreased BP, diminished thrombus formation in fi ne capillaries and arterioles, demonstrated the anticoagulant properties, partially improved endothelial dysfunction of small renal arteries, and up-regulated the glomerular filtration.

Topics: Animals; Anticoagulants; Blood Pressure; Hypertension; Magnetic Resonance Imaging; Naphthoquinones; Rats; Rats, Wistar; Renal Artery

Guanosine 5'-triphosphate cyclohydrolase-1 (GTPCH-1) is a rate-limiting enzyme in de-novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) coupling. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is crucial for GTPCH-1 preservation, and tumor suppressor kinase liver kinase B1 (LKB1), an upstream kinase of AMPK, is activated by NAD-dependent class III histone deacetylase sirtuin 1 (SIRT1)-mediated deacetylation. β-Lapachone has been shown to increase cellular NAD/NADH ratio via. quinone oxidoreductase 1 (NQO1) activation. In this study, we have evaluated whether β-lapachone-induced NQO1 activation modulates blood pressure (BP) through preservation of GTPCH-1 in a hypertensive animal model.. Spontaneously hypertensive rats (SHRs), primary aortic endothelial cells, and endothelial cell line were used to investigate the hypotensive effect of β-lapachone and its action mechanism. β-Lapachone treatment dramatically lowered BP and vascular tension in SHRs and induced eNOS activation in endothelial cells. Consistent with these effects, β-lapachone treatment also elevated levels of both aortic cGMP and plasma nitric oxide in SHRs. Meanwhile, β-lapachone-treated SHRs showed significantly increased levels of aortic NAD, LKB1 deacetylation, and AMPK Thr phosphorylation followed by increased GTPCH-1 and tetrahydrobiopterin/dihydrobiopterin ratio. In-vitro study revealed that AMPK inhibition by overexpression of dominant-negative AMPK nearly abolished GTPCH-1 protein conservation. Enhanced LKB1 deacetylation and AMPK activation were also elicited by β-lapachone in endothelial cells. However, inhibition of LKB1 deacetylation by blocking of NQO1 or SIRT1 blunted AMPK activation by β-lapachone.. This is the first study demonstrating that eNOS coupling can be regulated by NQO1 activation via LKB1/AMPK/GTPCH-1 modulation, which is possibly correlated with relieving hypertension. These findings provide strong evidence to suggest that NQO1 might be a new therapeutic target for hypertension.

Topics: AMP-Activated Protein Kinases; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Cell Line; Cells, Cultured; Endothelial Cells; Enzyme Activation; GTP Cyclohydrolase; Humans; Hypertension; Male; Mice; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Nitric Oxide Synthase Type III; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Sirtuin 1; Vasodilation

Angiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. β-lapachone (βL) has been shown to increase cellular NAD(+)/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by βL modulates BP through regulation of ACE shedding in an animal model of hypertension.. Spontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which βL exerts a hypotensive effect. In vitro studies revealed that βL significantly increased intracellular Ca(2+) ([Ca(2+)]i) levels and CaMKII Thr(286) phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca(2+)]i level changes through intracellular Ca(2+) chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca(2+)]i levels and CaMKII phosphorylation, but also βL-mediated decrease in ACE shedding. The effect of βL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, βL reduced BP following increase of CaMKII Thr(286) phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma.. This is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control.

Topics: Animals; Blood Pressure; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cells, Cultured; Humans; Hypertension; Male; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Peptidyl-Dipeptidase A; Phosphorylation; Rats; Rats, Inbred SHR

Hypertension is one of the most common human diseases worldwide, and extensive research efforts are focused upon the identification and utilizing of novel therapeutic drug targets. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important regulator of blood pressure (BP). β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase (NQO1), increases the cellular NAD(+)/NADH ratio via the activation of NQO1. In this study, we evaluated whether βL-induced activation of NQO1 modulates BP in an animal model of hypertension.. Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of βL and its mode of action. βL treatment stimulated endothelium-dependent vascular relaxation in response to acetylcholine in aorta of SHR and dramatically lowered BP in SHR, but the hypotensive effect was completely blocked by eNOS inhibition with ω-nitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in βL-treated SHR. In vitro studies revealed that βL treatment elevated the intracellular NAD(+)/NADH ratio and concentration of free Ca(2+) ([Ca(2+)]i), and resulted in Akt/AMP-activated protein kinase/eNOS activation. These effects were abolished by NQO1 siRNA and [Ca(2+)]i inhibition through a ryanodine receptor blockade.. This study is the first to demonstrate that NQO1 activation has a hypotensive effect mediated by eNOS activation via cellular NAD(+)/NADH ratio modulation in an animal model. These results provide strong evidence suggesting NQO1 might be a new therapeutic target for hypertension.

Topics: Acetylcholine; AMP-Activated Protein Kinases; Animals; Antihypertensive Agents; Blood Pressure; Calcium; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; Humans; Hypertension; Male; Mice; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; RNA Interference; Time Factors; Transfection; Vasodilation; Vasodilator Agents

Pin1 is a peptidyl prolyl cis-trans isomerase that only binds to and isomerizes phosphorylated serine/threonine-proline motifs, inducing conformational changes that alter target protein function and phosphorylation. We have shown previously that deficiency of another peptidyl prolyl isomerase, FK506 binding protein 12/12.6, alters endothelial NO synthase phosphorylation and causes endothelial dysfunction and hypertension. Endothelial NO synthase contains the Pin1 binding sequence at (p)serine 116-proline 117 and phosphorylation of endothelial NO synthase serine 116 inhibits NO production; however, whether Pin1 deficiency alters vascular function and blood pressure is unknown. We hypothesized that Pin1 isomerizes p-endothelial NO synthase serine 116, which enables dephosphorylation and stimulates NO production. Immunoprecipitation of endothelial NO synthase and probing for Pin1 in rat aortic endothelial cells confirmed the interaction between the two. Pin1 knockdown via small interfering RNA or inhibition by juglone increased endothelial NO synthase serine 116 phosphorylation and prevented vascular endothelial growth factor-induced serine 116 dephosphorylation in endothelial cells. Acute treatment of isolated mouse aortas with juglone increased endothelial NO synthase serine 116 phosphorylation and decreased NO production and relaxation responses. Mice treated with juglone for 2 weeks, as well as Pin1 knockout mice, exhibited increased aortic endothelial NO synthase serine 116 phosphorylation, endothelial dysfunction, and hypertension. These data demonstrate that Pin1 binds endothelial NO synthase and enables dephosphorylation of serine 116, which increases NO production and endothelium-dependent dilation, leading to blood pressure maintenance.

Topics: Amino Acid Substitution; Animals; Aorta; Binding Sites; Blood Pressure; Cells, Cultured; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; Immunoblotting; Immunoprecipitation; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; Nitric Oxide; Nitric Oxide Synthase Type III; Peptidylprolyl Isomerase; Phosphorylation; Protein Binding; Rats; RNA Interference; Serine; Vasodilation

Topics: Animals; Anti-Bacterial Agents; Blood Pressure; Catechol O-Methyltransferase Inhibitors; Chemical Phenomena; Chemistry; Hypertension; Lethal Dose 50; Naphthoquinones; Rats; Streptomyces

Topics: Antifibrinolytic Agents; Essential Hypertension; Humans; Hypertension; Naphthoquinones; Vitamin K

Topics: Antifibrinolytic Agents; Humans; Hypertension; Naphthoquinones; Papaverine; Retinoids; Vitamin K

Topics: Antifibrinolytic Agents; Hypertension; Naphthoquinones; Retinoids; Vitamin K

Topics: Antifibrinolytic Agents; Blood Pressure; Blood Pressure Determination; Hypertension; Naphthoquinones; Retinoids; Vitamin K

Topics: Antifibrinolytic Agents; Blood Pressure; Humans; Hypertension; Hypertension, Renal; Liver; Naphthoquinones; Oils; Vitamin A; Vitamin K; Vitamins